Jenny Nobes
Case history
A 65-year-old man presented to the colorectal surgical team with a 3-month history of progressive rectal pain and tenesmus. He had had no significant previous illnesses. Rectal examination revealed a hard, craggy, obstructing mass. Clinical examination was otherwise unremarkable. His ECOG performance status was 1. He was investigated with a CT scan of the abdomen and pelvis and MRI of the pelvis (Fig. 16.1).
Fig. 16.1
Question
1. What does the MRI scan (Fig. 16.1) show?
Answer
1. What does the MRI scan (Fig. 16.1) show?
There is an extensive locally advanced prostatic tumour extending posteriorly to involve the anterior rectal wall and the external sphincter on the right. There is bone marrow heterogeneity in both inferior pubic rami, raising the possibility of metastases. The images provided do not demonstrate any enlarged lymph nodes.
Subsequently, he underwent a defunctioning colostomy and rectal biopsy. Histology showed a poorly differentiated carcinoma with no gland formation. Immunohistochemical staining demonstrated a diffuse strong membranous and paranuclear positivity with pancytokeratin with focal dot-like positivity, and diffuse cytoplasmic positivity with prostate-specific antigen (PSA). CD56, CD3, CD20, S100, chromogranin, TTF-1, CDX2, MyoD1, desmin, CK7, CK20, and CEA were negative.
Questions
2. How would you interpret the histology and how would you investigate further?
3. What would your initial treatment plan be?
Answers
2. How would you interpret the histology and how would you investigate further?
Immunohistochemistry suggests a poorly differentiated prostate carcinoma based upon PSA staining and both CK7 and CK20 negativity. A colorectal tumour is less likely because CEA and CK20 would be expected to be positive. Urothelial malignancies commonly stain with both CK7 and CK20.
He should have a serum PSA, FBC, and renal and bone biochemistry. To complete his skeletal staging an isotope bone scan is necessary, since he has already been shown to have possible bone metastases on MRI. It would be useful to also assess for deposits in his calvarium and appendicular skeleton with plain X-rays, given the high frequency of bone metastases with advanced prostate cancer.
3. What would your initial treatment plan be?
The mainstay of treatment for advanced prostate cancer is androgen deprivation therapy. This man is hormone-naïve. Therefore, he should initially be commenced on either luteinizing hormone releasing hormone (LHRH) analogues covered with anti-androgens to prevent testosterone flare, or a LHRH antagonist such as degarelix.
Palliative radiotherapy to alleviate his rectal pain should also be considered once testosterone suppression therapy is initiated. CT-guided virtual simulation would be required to encompass the pelvic soft tissue mass, treating to a dose such as 30Gy in 10 daily fractions over 2 weeks, given his good performance status.
Consideration should be given to a referral for specialist palliative care input given his new diagnosis of symptomatic advanced prostate cancer with the psychological impact of requiring a colostomy.
His serum PSA measured 483μg/L prior to commencement of androgen deprivation therapy with other blood parameters being in the normal range. The bone scan demonstrated abnormal increased tracer uptake within the skull, cervical, thoracic and lumbar spine, both scapulae, the right humerus, multiple ribs, pelvis, and both proximal femora. There was no other soft tissue disease demonstrated on CT.
After 3 months of hormonal therapy his PSA reached a nadir of 50μg/L, rising shortly thereafter to 150μg/ml despite the addition of an anti-androgen. Synchronously, he began to develop lower back pain with a bilateral radicular element. On examination he had full power in his lower limbs, normal reflexes, and no sensory deficit. His anal sphincter tone was preserved, and there was no perineal anaesthesia.
An urgent MRI (Fig. 16.2) of the whole spine was performed. CT staging revealed no visceral or nodal metastases. His ECOG performance status was 1.
Fig. 16.2
Questions
4. What does the MRI scan (Fig. 16.2) show?
5. What would your initial management be based on these radiological findings?
6. Following this, what is your approach to systemically managing his prostate cancer, and what is the evidence base for this?
7. What are ‘skeletal-related events’ (SREs), and how would you reduce the risk of any further SREs?
8. What would you estimate his prognosis to be?
9. What would you advise him if he asks about prostate cancer screening for his sons?
Answers
4. What does the MRI scan (Fig. 16.2) show?
The MRI scan shows a large metastatic deposit involving the L2 vertebral body extending posteriorly into the central canal and compressing the cauda equina, with no cerebrospinal fluid around the nerve roots at this level.
5. What would your initial management be based on these radiological findings?
He should be commenced urgently on high-dose dexamethasone, e.g. 8mg twice daily, with a proton pump inhibitor for gastric protection. He has no neurological deficit so far from his cauda equina compression, has a good performance status, and has no extra-skeletal disease. His case should therefore be discussed with the spinal surgical team, and urgent spinal decompression and stabilization recommended to preserve his mobility.
Post-operatively, radiotherapy should be considered to the lumbar spine to reduce the risk of further neurological compromise at this level. A dose of 20Gy in five fractions would be one standard.
6. Following this, what is your approach to systemically managing his prostate cancer, and what is the evidence base for this?
Now that his prostate cancer has started to become hormone-refractory, he should be commenced on systemic chemotherapy with docetaxel 75mg/m2 every 21 days for a maximum of 10 cycles, plus prednisolone 5mg twice daily. In 2004, the TAX 327 study reported a better survival with this regimen (18.9 versus 16.5 months) compared with mitoxantrone (Tannock et al. 2004). This regimen was therefore approved by NICE in 2006. An update of that study (Berthold et al. 2008) confirmed the significantly prolonged survival after 3-weekly docetaxel plus prednisolone than with mitoxantrone plus prednisolone (19.2 versus 16.3 months, P = 0.004).
Options for subsequent therapeutic lines would include abiraterone 1000mg daily until progression, or cabazitaxel 25mg/m2 every 21 days for 10 cycles. A benefit in OS for both regimens has been reported in the COU-AA-301 and TROPIC trials, respectively (de Bono et al. 2010, 2011). The choice of regimen would depend on his performance status, bone marrow function, and previous response to taxane-based chemotherapy. At each stage, he should also be considered for entry into a clinical trial since there are several novel agents under investigation for advanced prostate carcinoma.
7. What are ‘skeletal-related events’ (SREs), and how would you reduce the risk of any further SREs?
SREs are defined as bone metastases resulting in pathological fracture, pain requiring radiotherapy to bone, surgery to bone, or malignant spinal cord compression. Radioactive strontium-89 and bisphosphonates such as intravenous pamidronate 90mg every 3–4 weeks are commonly prescribed in this clinical situation. However, the evidence for a delay in time to SRE and reduction in the number of SREs has only been demonstrated with intravenous zoledronic acid 4mg and the novel RANK ligand inhibitor denosumab, which is administered subcutaneously every 4 weeks.
This patient should therefore be considered for either zoledronic acid or denosumab in conjunction with his chemotherapy. Prior to commencement, he should undergo a baseline dental examination due to the approximate 10% risk of osteonecrosis of the jaw. He should also be prescribed oral calcium supplements to avoid the development of hypocalcaemia, providing that his serum-corrected calcium is not elevated.
8. What would you estimate his prognosis to be?
This depends in any individual on the response to further lines of systemic therapy. Based on the median survival advantages of taxane-based chemotherapy and abiraterone, an estimate of 12–24 months would be reasonable.
9. What would you advise him if he asks about prostate cancer screening for his sons?
The role of PSA screening has yet to be fully established. Large population-based screening studies in the United States and Scandinavia have reported a reduction in prostate cancer mortality, but with high numbers needed to screen before a life is saved. Nevertheless, in the UK, men over the age of 50, or over the age of 40 with a history of prostate cancer in a first-degree relative, are entitled to informed PSA testing. The risk of receiving a false negative or false positive result should be discussed, as should the options for management of early disease, including active surveillance.
Further reading
Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Journal of Clinical Oncology 2008; 26: 242–245.
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. The Lancet 2010; 376: 1147–1154.
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. New England Journal of Medicine 2011; 364: 1995–2005.
Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncology 2012; 13: 983–992.
Ilic D, O’Connor D, Green S, Wilt TJ. Screening for prostate cancer: an updated Cochrane systematic review. BJU International 2011; 107: 882–891.
Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. The Lancet 2005; 366: 643–648.
Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002; 94: 1458–1468.
Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. The Lancet 2012; 379: 39–46.
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New England Journal of Medicine 2004; 351: 1502–1512.